U.S. patent number 6,294,200 [Application Number 08/795,382] was granted by the patent office on 2001-09-25 for pharmaceutical tablet suitable to deliver the active substance in subsequent and predeterminable times.
This patent grant is currently assigned to Jagotec AG. Invention is credited to Ubaldo Conte, Lauretta Maggi.
United States Patent |
6,294,200 |
Conte , et al. |
September 25, 2001 |
Pharmaceutical tablet suitable to deliver the active substance in
subsequent and predeterminable times
Abstract
Pharmaceutical tablet, capable of delivering the active
substance or the active substances, according to a predeterminable
release profile, comprising a core with an external partial coating
in which said core consists of 3 layers, wherein the upper layer
contains an amount of the active substance with suitable
excipients, the intermediate layer consists of polymeric material
with retarding barrier function and the lower layer contains the
remaining amount of the active substance with suitable excipients
and said external coating consists of controlled permeability
polymeric materials, applied by compression to the lower surface
and to the lateral surface of the core.
Inventors: |
Conte; Ubaldo (Busto Arsizio,
IT), Maggi; Lauretta (Pavia, IT) |
Assignee: |
Jagotec AG (Hergiswil,
CH)
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Family
ID: |
11373151 |
Appl.
No.: |
08/795,382 |
Filed: |
February 4, 1997 |
Foreign Application Priority Data
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Feb 6, 1996 [IT] |
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MI96A0210 |
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Current U.S.
Class: |
424/472; 424/464;
424/474; 424/475 |
Current CPC
Class: |
A61K
9/2072 (20130101); A61K 9/209 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61K 9/24 (20060101); A61K
009/24 (); A61K 009/20 (); A61K 009/28 (); A61K
009/30 () |
Field of
Search: |
;424/464,472,474,475 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1022171 |
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Mar 1966 |
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GB |
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1346609 |
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Feb 1974 |
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GB |
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Primary Examiner: Dodson; Shelley A.
Attorney, Agent or Firm: Leydig, Voit & Mayer, Ltd
Claims
What is claimed is:
1. A tablet for pharmaceutical use suitable to release the active
substances in subsequent and predetermined times, comprising a
three layered core covered by a partial coating layer, said core
having the following structure:
an upper layer consisting of active substance and suitable
excipients to allow a fast release of the active substance when the
tablet comes into contact with an aqueous medium;
an intermediate layer whose composition comprises polymeric
material suitable to form a barrier able to determine a time
interval between the release of the active substance contained in
the upper layer and the active substance contained in the lower
layer,
a lower layer comprising one or more active substances and having
the same or a different composition as the upper layer, said lower
layer allowing the controlled release of said active
substances;
and wherein said partial coating layer consists of granulated
polymeric substances, adjuvant substances and plasticizing agents
applied by compression on the whole lateral surface and on the
lower base of said three layered core thus forming an impermeable
barrier which resists dissolution for a predetermined period of
time while allowing for the release of the active substance both
from the upper layer and from the lower layer, said polymeric
substances being selected from hydroxypropylmethylcellulose having
viscosity between 4,000 and 100,000 cP when measured at 20.degree.
C. in a 2% aqueous solution.
2. A tablet for pharmaceutical use according to claim 1 wherein the
adjuvant substance used in the formulation of the partial coating
layer is polyvinylpyrrolidone.
3. The tablet as claimed in claim 1, wherein said polymeric
substances of said partial coating are present in a percentage of
from 5 to 90% with respect to the total weight of said coating.
4. The tablet as claimed in claim 1, wherein said partial coating
forms from 5 to 70% of the total weight of the tablet and shows a
thickness of from 0.5 to 4.0 mm.
5. The tablet as claimed in claim 1, wherein said polymeric
substance of said partial coating is hydroxypropylmethylcellulose
having a viscosity of 4,000 cP.
6. The tablet as claimed in claim 1, wherein said polymeric
substance of said partial coating is hydroxypropylmethylcellulose
having a viscosity of 15,000 cP.
7. The tablet as claimed in claim 1, wherein said polymeric
substance of said partial coating is hydroxypropylmethylcellulose
having a viscosity of 100,000 cP.
Description
PRIOR ART
In the field of pharmaceutical technology, manifold are the kinds
of tablets manufactured in the last years in order to obtain the
release of the active substance vehiculated into them at a constant
rate in time. These tablets may determine a prolonged "therapeutic
covering" that is the maintenance of therapeutically effective
plasmatic levels of the active substance.
Examples of such embodiments are the so called "reservoir" systems,
the "OROS" osmotic pumps and the "push-pull" systems, such as those
for example described in the U.S. Pat. No. 4,160,020 (1979). These
systems, correctly working, imply the advantages of a possible
reduction of the daily total dosage with respect to the traditional
pharmaceutical forms and of a posological simplification and
therefore a better acceptability for the patient.
Together with these advantages, there are both structural and
functional drawbacks, which may drastically limit and/or prevent
from using for long periods said systems.
The most serious disadvantages reside in that their preparation
encompasses the use of rather complex polymeric materials; for
example the OROS osmotic pump coating consists of insoluble
polymeric material which is moreover not biodegradable in the
gastrointestinal tract and this may cause accumulation phenomena in
the intestine of the exhausted coatings with possible intestinal
obstruction.
Lower attention has been paid to the realization of pulsating
release pharmaceutical forms, in other words systems capable of
releasing one or more active substances at subsequent pulses
according to a program which takes into account the circadian
rhythms of particular pathological symptoms.
A pharmaceutical form belonging to this type is described in the
U.S. Pat. No. 4,865,849, in which a three layers pharmaceutical
tablet, is characterized in that two out of these 3 layers are
coated with a polymeric material impermeable and insoluble in
aqueous fluids having acid pH, but soluble in an alkaline
medium.
This tablet, even though innovative, cannot be manufactured on an
industrial scale by using the current productive technology.
An improvement to this therapeutic system is represented by U.S.
Pat. No. 5,487,901, wherein a tablet engineered for a release in
subsequent times of the active substances is produced by:
a) preparing a tablet having three overlapping layers and wherein
the upper layer comprises an active substance, the intermediate
layer optionally contains the same or a different active substance
from that contained in the upper layer, but has essentially the
function of a barrier layer, finally the lower layer contains an
active substance. In this three layers tablet the intermediate
layer (barrier) is able to determine the time interval between the
release of the first and the second dose of the drug contained in
the upper and lower layers respectively.
b) completely coating the tablet by means of a film consisting of
an impermeable polymeric material.
c) removing the polymeric coating from the upper surface
(recognizable since it shows a prominent portion) of the tablet by
abrasion thus allowing the immediate release of the active
substance quantity contained in said upper layer.
Also this realization shows nevertheless productive drawbacks
determined by the fact that, during the abrasion phase, a part of
the active substance contained in the upper layer is removed with
possible negative repercussions on the uniformity of the content of
the tablets. A further complication may reside in the polymeric
material used for the coating, which, although being biocompatible
and biodegradable, may request, for the biodegradability, a
prolonged period of time and cause the possible persistence of the
empty coating in the final tract of the intestine.
SUMMARY
The pharmaceutical tablet capable of releasing the active substance
in subsequent and predeterminable times according to the present
invention allows to overcome the drawbacks of the prior art. Said
tablet is characterized by the following structure:
a) a core consisting of three layers and obtained by compression,
in which
the upper layer contains an active substance which is immediately
released when the tablet comes into contact with an aqueous medium
or with gastric or intestinal fluid;
the intermediate layer optionally containing the active substance
has a suitable composition to form a barrier able to determine a
time interval between the release of the active substance contained
in the upper layer and the one contained in the lower layer;
the lower layer may present the same or a different formulation
from that of the upper layer, the same or a different active
substance from that contained in the upper layer, and it may be
formulated to have the release of the active substance with a
prefixed kinetics;
b) a polymeric coating of the lower and lateral surface of said
core, optionally coating an active substance, obtained by
compression, able to form a barrier impermeable to the aqueous
medium for a predeterminable period of time.
The tablet so obtained may be optionally further coated by a
polymeric film soluble in water or in aqueous fluids.
This tablet is prepared by the following procedure:
in the first step the three layers core is produced by a
compression procedure;
in the second step the core is coated by compression on the lower
and lateral surface with suitable polymeric materials having
controlled permeability formulated with excipients able to give the
mass suitable compressibility characteristics.
According to a further embodiment of the present invention the core
consists of two layers, wherein the upper layer is the
barrier-layer and the lower layer contains the fast release active
substance, said tablet being covered by said impermeable coating on
the lateral and lower surface while on the upper surface a layer
containing the fast release active substance is applied.
According to another further embodiment of the present invention
the three layers core is characterized by being covered on the
lateral and the lower surface by said impermeable coating, whereas
on the upper surface of the upper layer comprising the fast release
active substance a further layer containing the fast release active
substance is applied.
BRIEF DESCRIPTION OF THE FIGURES
The tablet according to the present invention is illustrated by the
following figures:
FIG. 1 shows the core of the tablet in which (1) represents the
upper layer, (2) represents the intermediate layer and (3)
represents the lower layer.
FIG. 2 shows a tablet having the coating (4) on the lower and
lateral surface;
FIG. 3 shows a tablet with a two layer core having the coating (4)
on the lower and lateral surface and the coating (5) on the upper
surface;
FIG. 4 shows a tablet having the coating (4) on the lower and
lateral surface and the coating (5) on the upper surface.
DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutical tablet object of the present invention allows
the release of active substances in subsequent and predeterminable
times and it is characterized by the following structure:
a) a core (FIG. 1) consisting of 3 layers in which:
the upper layer (1) contains an active substance vehiculated with
excipients able to assure a fast release of the active substance
when the tablet comes into contact with an aqueous medium or with
gastric or intestinal fluid;
the intermediate layer (2), or barrier-layer, shows a composition
based on biocompatible and biodegradable polymeric materials able
to form a barrier which determines a time interval between the
release of the active substance contained in the upper layer (1)
and the one contained in the lower layer (3); said intermediate
layer preferably does not contain the active substance; in any case
said intermediate layer acts as a "timer" for the release of the
substance contained in the lower layer. Said barrier layer has
fundamentally the task of slowly (in a time interval programmable
"in vitro") interacting with the dissolution medium, thus
protecting the third layer from the contact with the dissolution
medium for a predeterminable period of time;
the lower layer (3) may have the same or a different composition
from that of the upper layer, contain the same or a different
active substance from the one contained in the upper layer, in any
case this layer is able to allow the release of the active
substance according to a program predeterminable by suitable in
vitro tests;
b) a coating (4) (FIG. 2) applied on the lower and lateral surface
of said core by a compression procedure, consisting of a polymeric
material able to form a layer impermeable to the aqueous medium for
a period of time predeterminable by suitable in vitro tests.
Said coating shows a strength to the erosion and/or to the
gelification and/or to the dissolution able to assure an adequate
protection of the core from the contact with the external medium
for the period of time necessary to the release of the active
substance both from the upper layer and from the lower layer.
The tablet according to the present invention may be produced in
other forms without going outside the scope and the limits of the
invention, for example as disclosed in FIGS. 3 and 4 wherein the
layers (1), (2), (3) and the coating (4) have the already described
meaning and the coating (5) contains an active substance and is
characterized by having a composition able to allow the fast
release of the active substance itself.
The tablets described in the present invention may be easily
produced using highly automated compression procedures, as far as
the preparation both of the core and of the coating are
concerned.
In particular the partially coated three layers core tablets
represented in FIG. 2 are produced by a compression procedure in
two distinct steps. In the first step the three layers core is
obtained by means of a compressing machine of Manesty-Layer-press
type.
In the second step said three layers core undergoes a partial
coating by using a suitably equipped (Kilian-Centra-Cota kind or
Korsch-Central Core Coater 3C) compressing machines. Both these
machines are able to take said cores and place them correctly and
centrally into the matrix where the granulate or the powder is
deposited for the partial coating of said core; subsequently the
machine automatically provides for the final compression for the
coating of the core for the obtainment of the tablet as represented
in FIG. 2.
By this process a tablet is prepared with a portion of the surface
of layer 1 (corresponding to the upper surface of said layer)
immediately available for the contact with aqueous liquids and then
able to quickly release the active substance while the remaining
portion of the tablet (corresponding to lateral surface of the
layers 1 and 2 and the lateral and lower surface of layer 3)
results homogeneously and regularly coated by a layer of polymeric
material impermeable to the aqueous medium for a specified period
of time. As already noticed the tablet may show other
configurations which are pointed out for example in the FIGS. 3 and
4.
In fact the central core may also consist of a two layer tablet,
that is the layer 2 with barrier functions and the layer 3
containing the active substance as illustrated in the FIG. 3. This
core is coated by compression, on the upper part by a fast
disintegration and dissolution coating 5 containing an active
substance quantity which is quickly released and on the lateral
surface of layer 2 whereas on the lateral and lower surface of
layer 3 by the coating 4 which forms a barrier impermeable for a
specified period of time.
In any case the tablet core according to the present invention has
a suitable geometrical shape to be subjected to the coating process
by compression.
The preferred realization of the tablet according to the present
invention is represented in FIG. 2, wherein the layer (1), quickly
disintegrable and/or soluble, when comes into contact with the
aqueous liquids (both "in vitro" and "in vivo") allows first the
release of the active substance, after the activation of the
process of hydration and progressive gelification/erosion of the
barrier layer 2 and, finally, after a time interval depending on
the composition and the thickness of said barrier layer 2, the
controlled release of the active substance contained in the layer
3.
For the formulation of said layer 1, beside the active substance,
suitable compounds are used to increase the disintegration of said
layer facilitating in this way the dissolution (fast release) of
the vehiculated active substance.
Said compounds are preferably selected from the group consisting of
cross-linked polyvinylpyrrolidone, hydroxypropylcellulose and
hydroxypropylmethylcellulose having low and medium molecular
weight, cross-linked sodium carboxymethylcellulose,
carboxymethylstarch, potassium methacrylate-divinylbenzene
copolymer, polyvinylalcohols, starches, starches derivatives,
microcryistalline cellulose and cellulosic derivatives, beta
cyclodextrine and generally dextrines derivatives, mannitol,
lactose, sorbitol and xylitol and mixtures thereof. Said substances
form from 1.0 to 90% the weight of the layer and, preferably, from
20 to 70%.
Moreover adjuvant substances consisting of the so called
effervescent mixtures may be used, namely substances able to
produce the fast disintegration of the layer when it comes into
contact with aqueous liquids and, preferably, with gastric
juice.
Among these substances we mention sodium and other alkali or
alkaline-earth metals carbonates and bicarbonates, glycocoll sodium
carbonate and other pharmaceutically acceptable salts capable of
producing effervescence in an acid environment.
Depending on the pH of the medium during the disintegration of the
layer, other substances such as citric, tartaric and fumaric acid
may be added to the tablet according to the present invention, in
order to determine the appearance of the "effervescence" and the
fast disintegration.
Also adjuvant substances normally employed in the pharmaceutical
technique may be used such as diluents, buffers, binders,
adsorbents, lubricants etc. and particularly starch, pregelified
starch, calcium phosphate, mannitol, lactose, sucrose, glucose,
sorbitol, microcristalline cellulose and binding agents such as
gelatin, polyvinylpyrrolidone, methylcellulose, starch,
ethylcellulose, arabic gum, tragacanth gum, magnesium stearate,
stearic acid, colloidal silica, glyceryl monostearate,
polyoxyethylenglycols having molecular weight from 400 to 50000,
hydrogenated castor oil, waxes and mono-di and tri-substituted
glycerides.
The formulation of the layer 2 or barrier layer, which forms the
element allowing to determine the time interval before the release
of the active substance contained in the layer 3, comprises
polymers, adjuvant and plasticizing substances.
The polymers of the barrier layer are preferably selected from the
group consisting of hydroxypropylmethylcellulose with molecular
weight ranging from 1,000 and 4,000,000, hydroxypropylcellulose
with molecular weight from 2,000 to 2,000,000,
carboxyvinylpolymers, polyvinyl alcohols, glucans, scleroglucans,
mannans, galactomannans, carrageenin and carrageenans, xanthans,
alginic acid and derivatives thereof, pectine, amylose, poly(methyl
vinyl ethers/maleic anhydride), carboxymethylcellulose and
derivatives thereof, ethylcellulose, methylcellulose and in general
cellulosic derivatives and mixtures thereof.
Said polymeric substances are present in a percentage ranging from
5 to 90% of the total weight of said layer and preferably range
from 50 to 90%.
The adjuvant substances are preferably selected from the group
consisting of glyceryl monostearate and derivatives thereof,
semi-synthetic triglycerides, semi-synthetic glycerides,
hydrogenated castor oil, glycerylpalmitostearate, glyceryl
behenate, cetilic alcohol, polyvinylpyrrolidone, glycerin,
ethylcellulose, methylcellulose, sodium carboxymethylcellulose,
mixtures thereof and other natural or synthetic substances well
known to anyone skilled in the field. For example magnesium
stearate, stearic acid, talc, sodium benzoate, boric acid,
polyoxyethylenglycols and colloidal silica are employed.
Moreover diluent, binding substances, lubricants, buffering agents,
anti-adherents, gliding substances and other substances capable of
giving said layer the desired characteristics maybe used, like
those used later-on in the examples.
The plasticizing substances are preferably selected from the group
consisting of hydrogenated castor oil, fatty acids, substituted
glycerides and triglycerides, polyoxyethylenglycols and derivatives
thereof having different molecular weight, ranging from 400 to
60,000. They have the function to give the barrier layer the
necessary elasticity and improve its compressibility, adhesion and
cohesion characteristics.
The adjuvant substances, in association with the previously
reported polymeric materials, are able to better define the
protection time exerted by the barrier, this interval ranging from
15 minutes to more than 6-8 hours according to the therapeutic
needs requested.
This layer 3 may have the same composition as the layer 1 and
contain the same or a different active substance from that
contained in layer 1 or may contain a mixture of more active
substances which are released after a determined time interval from
the release of the active substance contained in layer 1.
Depending on the therapeutic requirements of the active substance
contained in said layer 3, the layer can contain substances able to
modify (to slow) the release of said active substances in a
predeterminable time interval by suitable in vitro tests.
According to the preferred embodiment illustrated in FIG. 2, the
three layer core is partially coated, by compression, with a
uniform coating 4 comprising polymeric material impermeable to
water and/or to aqueous fluids for the period of time needed for
the release of the active substance both from the layer 1 and from
the layer 3. Said period of time is predeterminable by in vitro
tests.
Said coating comprises also adjuvant substances, plasticizing
substances, lubricants, antiadherents etc. namely substances
capable of giving good mechanical and workability
characteristics.
The polymeric material for said coating is preferably selected from
the group consisting of: hydroxypropylmethylcellulose having
molecular weight ranging from 1,000 to 4,000,000,
hydroxypropylcellulose having molecular weight ranging from 2,000
to 2,000,000, carboxyvinyl polymers, polyvinylalcohols, glucans,
scleroglucans, mannans, galactomannans, carrageenin and
carrageenans, xanthans, alginic acid and salts thereof with alkali
and alkaline-earth metals, pectine, amylose and derivatives
thereof, poly (methyl vinyl ethers/maleic anhydride),
carboxymethylcellulose and derivatives thereof, ethylcellulose,
methylcellulose, acrylic and methacrylic copolymer (with different
solubility characteristics dependent or independent from the pH of
the medium), cellulose acetophthalate, cellulose acetopropionate,
cellulose trimellitate and other natural synthetic and/or
semisynthetic derivatives of cellulose, methylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose and
derivatives thereof, and mixture thereof.
Said polymeric substances are present in a percentage of from 5 to
90% of the total weight of said coating and preferably from 40 to
90%.
In the formulation of the coating adjuvant substances are used
preferably selected from the group consisting of glyceryl
monostearate and semi-synthetic triglycerides derivatives,
semi-synthetic glycerides, hydrogenated castor oil,
glycerylpalmitostearate, glyceryl behenate, cetilic alcohol,
polyvinylpyrrolidone, glycerin, ethylcellulose, methylcellulose,
sodium carboxymethylcellulose and other natural or synthetic
substances well known to anyone skilled in the field. For example
magnesium stearate, stearic acid, talc, sodium benzoate, boric
acid, polyoxyethylenglycols and colloidal silica, are used.
Moreover plasticizing substances are used preferably selected from
the group consisting of hydrogenated castor oil, fatty acids,
substituted glycerides and triglycerides, polyoxyethylenglycols and
derivatives thereof having different molecular weight, normally
ranging from 400 to 60,000 and mixture thereof.
They have the function to impart the material forming the coating
the necessary elasticity and improve the compressibility thereof,
adhesion and cohesion characteristics.
Moreover diluents, binding agents, lubricants, buffering,
antiadherents, gliding substances and other substances able to give
said layer the requested characteristics may be used like those
disclosed later-on in the examples.
Acting as reported above, tablets may be obtained coated by
compression in any part of the surface except for the upper face,
as reported in FIG. 2. This means that the whole surface of the
core results out to be impermeable to aqueous liquids except the
upper face.
The tablets so obtained may undergo a further filming process,
according to the traditional procedures, using a polymeric coating
easily soluble and/or dispersible in water and/or in aqueous fluids
depending on the pH of the medium, which does not modify the
release characteristics of the finished system. Said polymeric
coating may be formed by natural polymers such as shellac, sandarac
gum or synthetic ones such as hydroxypropylmethyl cellulose,
hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, the
acrylic and methacrylic copolymer (with different solubility
characteristics dependent or independent from the pH of the
medium), cellulose acetophthalate, cellulose acetopropionate,
cellulose trimellitate and other derivatives well known to those
skilled in the field.
If the coating film is gastroresistant and enterosoluble, the
release of the active substance vehiculated into said first layer,
can only occur at the duodenal level and the release of the active
substance contained in the third layer may occur at the level of
the distal part of the intestinal tract (at the colon level). Said
coating involves the whole surface of the tablet and it is applied
by using the basin or the fluidized bed technique.
As better pointed out in the examples, the tablet according to the
invention coming into contact with water and/or gastric fluid
and/or intestinal fluid is able to release immediately a first part
of the active substance while the second part of the active
substance is released in subsequent times depending on the
characteristics of the barrier layer.
The preferred size of the various components of the tablet are the
following:
core diameter: 4-12 mm, preferably 6-9 mm
thickness of the layers 1 and 3: 2-8 mm, preferably 3-4 mm
thickness of the layer 2: 0.4-4.0 mm, preferably 0.8-2.0 mm.
The outer coating shows a thickness of from 0.5 to 4.0 mm but
preferably from 1.0 to 2.0 mm and it corresponds to 5-70% by weight
of the total tablet weight.
These measures are absolutely indicative and not binding, since the
tablets according to the present invention may have different
geometrical shapes such as oval, ovoidal, ellipsoidal or
asymmetrical shape.
The active substance which may be employed in the tablets according
to the present invention is any substance having biopharmaceutical
and/or pharmacodynamical variations dependent on the circadian
cycle and the substances able to fulfill their therapeutic and/or
protective action against pathological manifestations which show
variations according to temporal and in particular circadian
rhythms; for example steroidal, non-steroidal anti-inflammatories
(NSAIDs) such as sodium diclofenac, indomethacin, ibuprofen,
ketoprofen, diflunisal, piroxicam, naproxen, flurbiprofen, sodium
tolmetin, substances having antibiotic activity such as ampicillin,
amoxycillin, cephradine, clavulanic acid, cefaclor, cefalexin,
cloxacillin, erythromycin, their salts and derivatives thereof,
substances having antimicrobic activity at the urogenital level
such as nitrofurantoin, nalidixic acid, oxolinic acid, pipemidic
acid, and derivatives thereof; sleep inducing substances and
tranquilizers such as diazepam, nitrazepam, flurazepam, oxazepam,
chlordiazepoxide, medazepam, lorazepam, active substances for the
prevention of anginous attacks and hypertensive attacks such as
diltiazem, trapidil, urapidil, benziodarone, dipyridamole,
lidoflazine, naphthydrofurile oxalate, perhexilline maleate,
oxyphedrine hydrochloride and antihistaminic and/or antiasthmatic
drugs such as ephedrine, terfenadine, theophylline,
chlorpheniramine, terbutaline, metaproterenol, aminophylline,
isoprenaline, salbutamol, methylprednisolone, dexamethasone
ibopamine and combinations thereof; antiviral drugs such as
acyclovir, gangliocyclovir, ribavirine, zoliuvidine or AZT; H2
antagonists anti-ulcer drugs: cimetidine, famotidine, nizatidine,
ranitidine, roxatidine, sucralfate; drugs active at cardiovascular
level such as: acebutol, metoprolol, atenolol, nadolol, oxprenolol,
bevantolol, bopindol, pindolol, labetolol, propranolol, mepindolol,
sotalol; calcium antagonists such as: amlodipine, nitrendipine,
nifedipine, nicardipine, verapamil; ACE-inhibitors: captopril,
enalapril, or substances having diuretic activity such as
hydrochlorothiazide, chlorthalidone, indapamide, piretamide,
xipamide; or organic nitrates: glyceryl trinitrate, isosorbide
dinitrate, isosorbide 5-mononitrate and antiparkinson drugs such as
Levodopa, carbidopa, benserazide.
The tablets according to the invention may be produced from
granular mixtures having a granulometry lower than 710 .mu.m using
the productive technologies currently in use and then by a
production process immediately transferable on industrial
scale.
The three layer core, is produced using rotating compressing
machines able to produce "multilayer" tablets such as for example
Manesty Layer-press (Liverpool, UK).
Normally the working pressure ranges from 800 to 5000 kg. The three
layers core is then coated applying the coating material by
compression, by using a rotating compressing machine, with a
pressure of from 800 to 5000 kg, as it will be better understood in
the examples. Optionally the tablet so obtained is completely
coated with a soluble film dependent on the pH of the medium.
EXAMPLE 1
Preparation of a series of (5,000) tablets as represented in FIG.
2, containing Ranitidine hydrochloride as active substance.
1-a--Preparation of the Granulate Containing the Active
Substance
A granulate is prepared which is used in the preparation of the
layers (1) and (3). Each layer, which contains 150 mg of active
substance, has the following unit composition:
Ranitidine HCl (U.S.P. grade) equal to 150 mg of ranitidine 167.4
mg Cornstarch (USP grade, C. Erba, Milan, I) 40.0 mg
Polyvinylpyrrolidone (Plasdone.sup.R K30, ISP, Wayne, NY, 4.0 mg
USA) Carboxymethyl starch (Explotab.sup.R, E. Mendell Co. Inc.,
35.0 mg Carmel, NY, USA) Magnesium stearate (USP grade, C. Erba,
Milan, I) 5.0 mg Total 239.4 mg
In a sigma mixer mod. Erweka K 5 type (Frankfurt a. M.--D),
suitable amounts of the active substance and cornstarch are mixed;
the mixture is wet by using a 10% (w/v) alcoholic solution of
polyvinylpyrrolidone and the homogeneously wet mass is forced onto
a 25 mesh (710 .mu.m) grid thereby obtaining a regular granulate
which is dried in a 40-45.degree. C. air circulation stove. The
granulate, dried up to a constant weight, is placed in a Turbula
T2A mod. (Bachofen--Basel--CH) powder mixer and added with
carboxymethylstarch and mixed for 20 minutes. Magnesium stearate is
then added to the mixture and the mixing is carried on for further
20 minutes. The granulate undergoes the compression stage as
described below.
1-b--Preparation of the Granulate for the Barrier Layer (2)
An amount of granulate necessary for the achievement of No. 5000
barrier layers having the following per cent composition is
prepared:
Hydroxypropylmethylcellulose (Methocel.sup.R E5 Premium, Colorcon,
76.5 Orpington, UK) Hydrogenated castor oil (Cutina HR, Henkel,
Dusseldorf, D) 19.0 Polyvinylpyrrolidone (Plasdone.sup.R K29-32
ISP, Wayne, NY, USA) 2.9 Green lacquer (Eigenmann Veronelli, Milan,
I) 0.1 Magnesium stearate (USP grade, C. Erba, Milan, I) 1.0
Colloidal silica (Syloid 244, Grace GmbH, Worms, D) 0.5 Total
100.0
In a sigma Erweka K5 type mod. (Frankfurt am M., D) mixer the
proper amounts of hydroxypropylmethyl cellulose (Methocel E 5:
apparent viscosity 5 cps), hydrogenated castor oil and green
lacquer are mixed; the mixture is wet with a 10% w/v
hydro-alcoholic solution of polyvinylpyrrolidone and the
homogeneously wet mass is forced onto a 25 mesh (710 .mu.m) grid,
thereby obtaining a regular granulate, of light green colour, which
is dried in a 40-45.degree. C. air circulation stove. The
granulate, dried up to a constant weight, is placed in a (Turbula
T2A mod.) powder mixer and added with magnesium stearate and
colloidal silica and mixed for 20 minutes. The granulate undergoes
the compression stage as described below.
1-c--Preparation of the Three Layer Cores (by compression)
The granulates obtained according to what reported above are loaded
in the three charging hoppers of a rotating compressing machine
suitable to produce three layers tablets (e.g. Manesty Layer-Press,
Liverpool, UK). In particular in the first and third hopper the
granulate described at point 1-a is loaded while the second hopper
is filled up with the granulate described at point 1-b.
The compressing machine is equipped with circular convex punches
having a diameter equal to 9 mm and R=12 mm. The machine is
adjusted in order to produce three layer cores formed by a first
239.4 mg amount of granulate containing the active substance (equal
to 150 mg of ranitidine) a 100 mg barrier layer (such an amount
being necessary to obtain a thickness of about 1.0 mm) and a second
239.4 mg quantity of granulate containing the active substance
(corresponding to 150 mg of ranitidine).
Operating at 3,000 kg pressure three layer cores having an average
weight equal to 578.8 mg containing two distinct quantities of
active substance (150 mg each), in the layer 1 and in the layer 3
are respectively obtained. The cores so obtained undergo a second
compression stage for the application of the partial coating using
the granulate described at point 1-d.
1-d--Preparation of the Granulate for the External Coating
An amount of granulate necessary for the achievement of No. 5000
coatings having, each, the following percentage composition is
prepared:
Hydroxypropylmethylcellulose 46.0 (Methocel.sup.R K4M, Colorcon,
Orpington, UK) Mannitol 46.0 Polyvinylpyrrolidone (Plasdone.sup.R
K29-32 Gaf Corp., 6.3 Wayne, NY, USA) Red + blue lacquer
(Eigenmann-Veronelli, Milan, I) 0.2 Magnesium stearate (USP grade,
C. Erba, Milan, I) 1.0 Colloidal silica (Syloid 244, Grace GmbH,
Worms, D) 0.5 Total 100.0
In a sigma Erweka K5 type mod. (Frankfurt am M., D) mixer the
proper amounts of hydroxypropylmethyl cellulose (Methocel K4M:
apparent viscosity 4000 cps), mannitol and red-blue lacquer are
mixed; the mixture is wet with a 10% w/v hydro-alcoholic solution
of polyvinylpyrrolidone and the homogeneously wet mass is forced
onto a 25 mesh (710 .mu.m) grid obtaining a regular granulate, of
violet color, which is dried in a 40-45.degree. C. air circulation
stove. The granulate, dried to a constant weight, is placed in a
(Turbula T2A mod.) powder mixer and added with magnesium stearate
and colloidal silica and mixed for 20 minutes. The granulate,
undergoes the compression stage as described below.
1-e--Partial Coating by Compression of the Cores
The granulate obtained according to point 1-d is loaded in the
first charging hopper of a rotating compressing machine suitable to
produce the so called dry-coated tablets (e.g. Kilian Centra-Cota
or Korsch-Central Core Coater 3C type). In order to obtain the
tablets illustrated in FIG. 2, the second hopper does not contain
granulate. the compressing machine is equipped with circular convex
punches having a diameter equal to 12 mm and R=12 mm. The machine
is adjusted to produce in-lay tablets with quantities of 220 mg of
granulate for the coating layer. The machine is likewise equipped
with a transfer system allowing the transfer of the three layer
cores prepared as pointed out at point 1-c and the exact
positioning in the matrix, in which the amount of granulate
necessary for the coating has already been supplied. Automatically
the machine provides for the perfect centering of said core and for
the progressive compression which enables the progressive sinking
of the core in the powder bed constituted by the granulate 1-d and
finally the achievement of the coated tablet.
Operating at about 3000 kg pressure the tablets are obtained
illustrated in FIG. 2 consisting of a three layers core (two out of
these layers contain 150 mg of ranitidine each) coated on the
surface except for the upper face of the layer 1.
1-f--Dissolution Test
In order to estimate the release characteristics of the tablets,
the equipment 2, paddle (described in USP XXII) is used operating
at 100 r.p.m. and using deionized water at 37.degree. C. as the
dissolution fluid. The release of the active substance is followed
by U.V. spectrophotometric determination at 313 nm using an
automatic sampling and reading system (Spectracomp 602, Advanced
Products--Milan, I).
The results are reported in Table I.
TABLE 1 % released TIME (min) active substance 10 41.0 20 47.5 30
50.0 60 51.3 90 54.9 120 72.6 150 88.5 180 95.1 210 98.1 240
99.8
It is possible to point out that from the tablets a fast release of
the first amount of active substance (47.5% of the total dose
contained into the tablets) in 20 minutes is obtained, an interval
of about 80 minutes during which a negligible amount of active
substance is released and the subsequent fast release of the second
quantity of active substance after 90 minutes from the beginning of
the dissolution test. Such a behaviour fully answers the aims of
the present invention.
EXAMPLE 2
Preparation of a series of tablets (5,000) as represented in FIG.
3, containing Ranitidine hydrochloride as the active principle.
A thickness of the barrier layer 2 able to determine a more
prolonged time interval between the release of the first and the
second quantity of active substance, with respect to what has been
reported in the Example 1 has been realized.
2-a--Preparation of the Granulate Containing the Active Substance
(Ranitidine hydrochloride)
The preparation is carried out as described in example 1 at point
1-a.
2-b--Preparation of the Granulate for the Barrier Layer 2
The preparation is carried out as reported in example 1 at point
1-b.
2-c--Preparation of Two Layer Cores (by compression)
The granulates obtained according to what reported at points 2-a
and 2-b are loaded into the two hoppers of a rotating compressing
machine suitable to produce two layer tablets (e.g. Manesty
Layer-Press, Liverpool, UK). In particular in the first hopper the
granulate described at point 2-a is loaded while the second hopper
is filled up with the granulate described at point 2-b.
The compressing machine is equipped with circular convex punches
having a diameter equal to 9 mm and R=12 mm. The machine is
adjusted to produce two layer cores, wherein the layer 3 formed by
239.4 mg of granulate containing the active substance (equal to 150
mg of ranitidine) and the barrier layer 2 consisting of 130 mg of
the relative granulate (such an amount being necessary to obtain a
thickness of about 1.2 mm). Two layer cores having an average
weight equal to 369.4 mg containing 150 mg of active substance are
obtained. The cores so obtained undergo a second compression stage
for the application of the coating again using the granulate
described at point 2-a for the coating 5 and the granulate
described at the point 2-d for the coating 4.
2-d--Preparation of the Granulate for the Coating
The preparation is carried out as reported in example 1 at point
1-d.
2-e--Coating by Compression of the Cores
The granulate obtained according to what described at point 2-d is
loaded into the first hopper of a rotating compressing machine
suitable to produce the so called dry-coated tablets (e.g. Kilian
Centra-Cota or Korsch-Central Core Coater 3C type), whereas, in the
second hopper the granulate is loaded containing the active
principle Ranitidine hydrochloride, described at point 2-a.
The compressing machine is equipped with circular convex punches
having a diameter equal to 12 mm and R=12 mm. The machine is
adjusted to produce dry-coated tablets as illustrated in FIG. 3, in
which the coating 4 consists of granulate described at the point
2-d and the coating 5 consists of the granulate described at point
2-a. The hopper feeding the transfer system of the cores is loaded
with the two layer cores prepared as indicated at point 2-c. The
machine provides for the transfer and the exact positioning of the
cores in the matrix into which the amount of granulate necessary
for the coating 4 has already been supplied. Automatically the
machine provides for the perfect centering of the cores, for a
precompression stage which enables the sinking of the core in the
granulate bed constituting the coating and for the loading of the
granulate for the coating 5 and then it provides for the final
compression of the system which allows the achievement of a tablet
as reported in FIG. 3. Operating as described in example 1 the
tablets consisting of a two layers core, coated by two different
kinds of granulate are thus obtained. The first, of impermeable
kind, covers the tablet except for the upper surface, while the
second one containing the active substance covers the upper
face.
2-f--Dissolution Test
The dissolution test is carried out as described in example 1 at
point 1-f.
The results are reported in Table II.
TABLE II TIME (min) % released 10 44.4 20 48.2 30 49.1 60 50.1 90
51.4 120 52.8 150 54.1 180 80.9 210 93.8 240 98.8
It is possible to point out that from the tablets of example 2 a
fast release of the first amount of active substance (49.1% of the
total dose contained into the system) in 30 minutes is obtained, an
interval of more than 2 hours during which a negligible amount of
active substance is released and the subsequent fast release of the
second amount of active substance after 2 hours and 30 minutes from
the beginning of the dissolution test. Such a behaviour fully
answers the aims of the present invention.
EXAMPLE 3
Preparation of a series of tablets (5,000) as represented in FIG.
2, containing sodium diclofenac as active substance.
3-a--Preparation of the Granulate Containing the Active
Substance
A granulate is prepared, according to the patterns farther on
described, which is used in the preparation of the layers 1 and 3.
Each layer, which contains 75 mg of active substance, has the
following unit composition:
Sodium diclofenac (Secifarma, Milan, I) 75.0 mg Cornstarch (C.
Erba, Milan, I) 90.0 mg Sodium lauryl sulfate (USP grade, C. Erba,
Milan, I) 0.2 mg Methylcellulose (Methocel A 4 C, Colorcorn
Orpington, UK) 0.4 mg Carboxymethyl starch (Explotab.sup.R, E.
Mendell Co., 6.0 mg Carmel, NY, USA) Crosslinked
polyvinylpyrrolidone (Polyplasdone XL, ISP, 3.8 mg Wayne, NY, USA)
Magnesium stearate (C. Erba, Milan, I) 1.0 mg Total 176.4 mg
In a sigma mixer mod. Erweka K 5 type (Frankfurt a. M.--D),
suitable amounts of the active substance and cornstarch are mixed;
the mixture is wet by a 1.3% w/v aqueous solution of
methylcellulose into which the sodium lauryl sulfate had been
previously dissolved; the homogeneously wet mass is forced onto a
25 mesh (710 .mu.m) grid obtaining a regular granulate which is
dried in a 40-45.degree. C. air circulation stove. The granulate,
dried to a constant weight, is placed in a Turbula T2A mod.
(Bachofen--Basel--CH) powder mixer and added with
carboxymethylstarch and crosslinked polyvinylpyrrolidone and mixed
for 20'. Magnesium stearate is then added to the mixture and mixing
is carried out for further 20 minutes. The granulate, analyzed as
far as the active principle content is concerned, undergoes the
compression stage as described below.
3-b--Preparation of the Granulate for the Barrier Layer 2
An amount of granulate necessary for the achievement of No. 5000
barrier layers having the following percentage composition is
prepared:
Hydroxypropylmethylcellulose (Methocel.sup.R E3 Premium, Colorcon,
76.5 Orpington, UK) Hydrogenated castor oil (Cutina HR, Henkel,
Dusseldorf, D) 19.0 Polyvinylpyrrolidone (Plasdone.sup.R K29-32
ISP, Wayne, NY, USA) 2.9 Green lacquer + blue lacquer (Eigenmann
Veronelli, Milan, I) 0.1 Magnesium stearate (USP grade, C. Erba,
Milan, I) 1.0 Colloidal silica (Syloid 244, Grace GmbH, Worms, D)
0.5 Total 100.0
In a sigma Erweka K5 type mod. (Frankfurt am M., D) mixer the
proper amounts of hydroxypropylmethyl cellulose (Methocel E 3:
apparent Viscosity 3 cps), hydrogenated castor oil, blue lacquer
and green lacquer are mixed; the mixture is wet with a 10% w/v
hydro-alcoholic solution of polyvinylpyrrolidone and the
homogeneously wet mass is forced onto a 25 mesh (710 .mu.m) grid
obtaining a regular granulate, of dark green colour, which is dried
in a 40-45.degree. C. air circulation stove. The granulate, dried
up to a constant weight, is placed in a (Turbula T2A mod.) powder
mixer and added with magnesium stearate and colloidal silica and
mixed for 20'. The granulate, undergoes compression as described
below.
3-c--Preparation of the Three Layer Cores (by compression)
The preparation is carried out as reported in example 1 at point
1-c. The compressing machine, equipped with circular convex punches
having a diameter equal to 9 mm and R=12 mm is adjusted to produce
three layers cores formed by a layer 1 having 176.4 mg of granulate
3-a containing the active substance (equal to 75 mg of diclofenac),
a layer 2 having 100 mg of granulate 3-b (such an amount being
necessary to obtain a thickness of about 1.0 mm) and a layer 3
having 176.4 mg of granulate 3-a containing the active substance
(equal to 75 mg of diclofenac). Operating as described, three
layers cores having an average weight equal to 452.8 mg containing
two distinct amounts of active principle (each corresponding to 75
mg), in layer 1 and in layer 3 are respectively obtained. The cores
so obtained undergo a second compression stage for the application
of the partial coating using the granulate described at point
3-d.
3-d--Preparation of the Granulate for the External Coating
The preparation is carried out as reported in example 1 at point
1-d.
3-e--Partial Coating by Compression of the Cores
The coating of the cores is carried out as reported in example 1 at
point 1-e.
Tablets, as illustrated in FIG. 2, are obtained consisting of a
three layers core (two out of these 3 layers contain 75 mg each of
diclofenac), coated on the surface except for the upper face of the
first layer characterized by a quick release of the active
principle.
3-f--Dissolution Test
In order to estimate the release characteristics of the tablets,
the experiment 2, paddle (described in USP XXII) is used operating
at 100 r.p.m. and using deionized water at 37.degree. C. as the
dissolution fluid. The release of the active substance is followed
by U.V. spectrophotometric determination at 276 nm using an
automatic sampling and reading system (Spectracomp 602, Advanced
Products--Milan, I).
The results are reported in Table III.
TABLE III TIME (min) % release 15 27.9 30 39.9 45 49.3 60 49.9 90
50.2 120 52.0 150 61.7 180 78.0 210 95.4 240 100.5
It is possible to point out that from the tablets a fast release of
the first amount of active substance (49.3% of the total dose) in
45 minutes is obtained, an interval of about 90 minutes during
which a negligible amount of active substance is released and the
subsequent fast release of the second amount of active substance
after 2.5 hours from the beginning of the dissolution test. Such a
behaviour fully answers the aims of the present invention.
EXAMPLE 4
Preparation of a series (5,000) of tablets as reported in example
3, containing sodium diclofenac as active principle, using a
different composition for the external coating.
4-a--Preparation of the Granulate containing the Active
Substance
The preparation is carried out as reported in example 3 at point
3-a.
4-b--Preparation of the Granulate for the Barrier Layer 2
The preparation is carried out as reported in example 3 at point
3-b.
4-c--Preparation of the Three Layer Cores (by compression)
The preparation is carried out as reported in example 3 at point
3-c.
4-d--Preparation of the granulate for the External Coating
An amount of granulate is prepared necessary for the achievement of
No. 5,000 coatings having, each, the following percentage
composition:
Hydroxypropylmethylcellulose (Methocel.sup.R K100M, 79.0 Colorcon,
Orpington, UK) Hydrogenated castor oil (Cutina HR, Henkel,
Dusseldorf, D) 13.3 Polyvinylpyrrolidone (Plasdone.sup.R K29-32 Gaf
Corp., 6.0 Wayne, NY, USA) Orange lacquer (Eigenmann-Veronelli,
Milan, I) 0.2 Magnesium stearate (USP grade, C. Erba, Milan, I) 1.0
Colloidal silica (Syloid 244, Grace GmbH, Worms, D) 0.5 Total
100.0
In a sigma Erweka K5 type mod. (Frankfurt am M., D) mixer the
proper amounts of hydroxypropylmethyl cellulose (Methocel K100M:
apparent viscosity 100000 cps), mannitol and orange lacquer are
mixed; the mixture is wet with a 10% w/v hydro-alcoholic solution
of polyvinylpyrrolidone and the homogeneously wet mass is forced
onto a 25 mesh (710 .mu.m) grid, thereby obtaining a regular
granulate, of orange colour, which is dried in a 40-45.degree. C.
air circulation stove. The granulate, dried to a constant weight,
is placed in a Turbula T2A mod. powder mixer and added with
magnesium stearate and colloidal silica and mixed for 20 minutes.
The granulate, undergoes compression as described below.
4-e--Coating by Compression of the Cores
The coating is carried out as reported in example 1 at point 1-e,
using the granulate described at point 4-d.
Tablets, as illustrated in FIG. 2, are obtained consisting of a
three layers (two out of these 3 layers contain 75 mg each of
diclofenac), coated on the surface except for the upper face
corresponding to the first layer showing fast release of the active
substance.
4-f--Dissolution Test
The test is carried out as described in the Example 3 at the point
3-f. The results are reported in Table IV.
TABLE IV TIME (min) % released 15 24.6 30 38.9 45 47.6 60 50.3 90
51.2 120 51.7 150 52.9 180 60.1 210 75.8 240 89.9 270 97.5 300
100.7
It is possible to point out that from the tablets a fast release of
the first amount of active substance (47.6% of the total dose
contained into the tablet) in 45 minutes is obtained, an interval
of about 2 hours during which a negligible amount of active
substance is released and the subsequent fast release of the second
amount of active substance after 2 hours and 30 minutes from the
beginning of the dissolution test. Such a behaviour fully answers
the aims of the present invention.
EXAMPLE 5
Preparation of a series of (5,000) tablets as represented in FIG.
2, containing ibuprofen as active substance.
5-a--Preparation of the Granulate Containing the Active
Substance
A granulate is prepared, according to the patterns farther on
described, which is used in the preparation of the layers 1 and 3.
Each layer, which contains 150 mg of active substance, has the
following unit composition:
Ibuprofen (Francis, Milan, I) 150.0 mg Cornstarch (C. Erba, Milan,
I) 44.8 mg Methylcellulose (Methocel A 4 C, Colorcon Orpington, UK)
0.8 mg Crosslinked polyvinylpyrrolidone (Polyplasdone.sup.R XL, 4.5
mg Gaf Corp., Wayne, NY, USA) Carboxymethylstarch (Explotab.sup.R,
Mendell, Carmel, NY, 11.2 mg USA) Magnesium stearate (C. Erba,
Milan, I) 1.9 mg Total 213.2 mg
In a sigma mixer mod. Erweka K 5 type (Frankfurt a. M.--D),
suitable amounts of the active substance and cornstarch are mixed;
the mixture is wet by a 1% (w/v) aqueous solution of
methylcellulose and the homogeneously wet mass is forced onto a 25
mesh (710 .mu.m) grid obtaining a regular granulate which is dried
in a 40-45.degree. C. air circulation stove. The granulate, dried
to a constant weight, is placed in a Turbula T2A mod.
(Bachofen--Basel--CH) powder mixer, added with crosslinked
polyvinylpyrrolidone, carboxymethylstarch and mixed for further
20'. Magnesium stearate is then added to the mixture and the mixing
is carried out for further 20 minutes. The granulate undergoes
compression as described below.
5-b--Preparation of the Granulate for the Barrier Layer 2
The preparation is carried out as reported in example 1 at point
1-b.
5-c--Preparation of the Three Layer Cores (by compression)
The granulate obtained according what previously reported are
loaded into the three hoppers of a rotating compressing machine
suitable to produce three layer tablets (e.g. Manesty Layer-Press,
Liverpool, UK). In particular in the first and in the third hopper
the granulate described at point 5-a is loaded; while the second
hopper is filled with the granulate described at point 5-b.
The compressing machine is equipped with circular convex punches
having a diameter equal to 9 mm and R=12 mm. The machine is
adjusted to produce three layers cores and precisely: layer 1
formed by 213.2 mg of granulate containing the active substance
(equal to 150 mg of ibuprofen), layer 2 constituted by 100 mg of
the granulate for the barrier layer (such an amount being necessary
to obtain a thickness of about 1.0 mm) and layer (3) constituted by
213.2 mg of granulate containing the active substance (equal to 150
mg of ibuprofen). Three layers cores are obtained having an average
weight equal to 526.4 mg containing two distinct amounts of active
substance (each amount of active substance corresponding to 150
mg). The cores so obtained undergo a second compression stage for
the application of the partial coating using the granulate
described at point 5-d.
5-d--Preparation of the Granulate for the External Coating
The preparation is carried out as reported in example 4 at point
4-d.
5-e--Coating by Compression of the Cores
The coating is carried out as reported in example 1 at point 1-e,
using the barrier granulate as described at point 5-d.
The tablets, as illustrated in FIG. 2, are obtained consisting of a
three layers core (two out of said three layers contain 150 mg each
of ibuprofen), coated on the surface except for the upper face
corresponding to the first layer showing the fast release of the
active substance.
5-f--Dissolution Test
In order to estimate the release characteristics of the tablets the
eqipment 2, paddle (described in USP XXII) is used operating at 100
r.p.m. and using simulated intestinal fluid (according to USP
XXIII), pH=7.5 at 37.degree. C. as the dissolution fluid. The
release of the active substance is followed by U.V.
spectrophotometric determination at 223 nm using an automatic
sampling and reading system (Spectracomp 602, Advanced
Products--Milan, I).
The results reported in Table V.
TABLE V TIME (min) % released 15 47.8 30 50.0 60 51.2 90 51.9 120
52.4 150 52.8 180 53.1 210 53.5 240 63.3 270 101.4 300 101.6
It is possible to point out that from the tablets a fast release of
the first quantity of active substance (50% of the total dose) in
30 minutes is obtained, an interval of about 3 hours during which a
negligible amount of active substance is released and the
subsequent fast release of the second quantity of active substance
after 3 hours and 30 minutes from the beginning of the dissolution
test. Such a behaviour fully answers the aims of the present
invention.
EXAMPLE 6
Preparation of a series of (5,000) tablets as illustrated in FIG.
2, containing ibuprofen as active substance.
6-a--Preparation of the Granulate Containing the Active Substance
for the Layers 1 and 3
The preparation is carried out as reported in example 5 at point
5-a.
6-b--Preparation of the Granulate for the Barrier Layer 2
An amount of granulate necessary for the achievement of No. 5000
barrier layers having the following percentage composition is
prepared:
Hydroxyrpropylmethylcellulose (Methocel.sup.R E50 Premium, 76.5
Colorcon, Orpington, UK) Hydrogenated castor oil (Cutina HR,
Henkel, Dusseldorf, D) 19.0 Polyvinylpyrrolidone (Plasdone.sup.R
K29-32 ISP, Wayne, NY, USA) 2.9 Yellow lacquer (Eigenmann
Veronelli, Milan, I) 0.1 Magnesium stearate (USP grade, C. Erba,
Milan, I) 1.0 Colloidal silica (Syloid 244, Grace GmbH, Worms, D)
0.5 Total 100.0
In a sigma Erweka K5 type mod. (Frankfurt am M., D) mixer the
proper amounts of hydroxypropylmethyl cellulose (Methocel E 50:
apparent Viscosity 50 cps), hydrogenated castor oil and yellow
lacquer are mixed; the mixture is wet with a 10% w/v
hydro-alcoholic solution of polyvinylpyrrolidone and the
homogeneously wet mass is forced onto a 25 mesh (710 .mu.m) grid
obtaining a regular granulate, of yellow colour, which is dried in
a 40-45.degree. C. air circulation stove. The granulate, dried to a
constant weight, is placed in a Turbula T2A mod. powder mixer and
added with magnesium stearate and colloidal silica and the mixing
is carried on for 20'. The granulate, undergoes compression as
described below.
6-c--Preparation of the Three Layer Cores (by compression)
The preparation is carried out as reported in example 5 at point
5-c, using for the barrier layer 2 the granulate described at point
6-b. Three layers cores having an average weight equal to 527.4 mg
containing two distinct amounts of active substance, each weighing
150 mg. The cores so obtained undergo a second compression for the
application of the external coating using the granulate described
at the point 6-d.
6-d--Preparation of the Granulate for the External Coating
An amount of granulate necessary for the achievement of No. 5,000
coatings having the following percentage composition is
prepared:
Hydroxypropylmethylcellulose (Methocel.sup.R K15M, 79.0 Colorcon,
Orpington, UK) Hydrogenated castor oil (Cutina HR, Henkel,
Dusseldorf, D) 13.3 Polyvinylpyrrolidone (Plasdone.sup.R K29-32,
ISP, Wayne, NY, USA) 6.0 Red lacquer (Eigenmann-Veronelli, Milan,
I) 0.2 Magnesium stearate (USP grade, C. Erba, Milan, I) 1.0
Colloidal silica (Syloid 224, Grace GmbH, Worms, D) 0.5 Total
100.0
In a sigma Erweka K5 type mod. (Frankfurt am M., D) mixer the
proper amounts of hydroxypropylmethyl cellulose (Methocel K15M:
apparent viscosity 15000 cps), mannitol and red lacquer are mixed;
the mixture is wet with a 10% w/v hydro-alcoholic solution of
polyvinylpyrrolidone and the homogeneously wet mass is forced onto
a 25 mesh (710 .mu.m) grid obtaining a regular granulate, of pink
colour, which is dried in a 40-45.degree. C. air circulation stove.
The granulate, dried to a constant weight, is placed in a (Turbula
T2A mod.) powder mixer and added with magnesium stearate and
colloidal silica and the mixing is carried on for 20'. The
granulate undergoes compression as described below.
6-e--Coating by Compression of the Cores
The coating of the cores is carried out as reported in example 1 at
point 1-e, using the granulate described at point 6-d.
Tablets, as illustrated in FIG. 2, are obtained consisting of a
three layers core (two out of three layers contain 150 mg each of
ibuprofen) coated on the surface except for the upper face
corresponding to the first layer showing the fast release of the
active substance.
6-f--Dissolution Test
The test is carried out as reported in example 5 at point 1-f. The
results are reported in Table VI.
TABLE VI TIME (min) % release 15 45.4 30 47.8 60 49.6 120 50.0 180
50.2 240 50.6 300 50.8 360 50.9 420 51.2 480 51.3 540 77.2 600 89.3
660 98.7 720 100.2
It is possible to point out that from the tablets a fast release of
the first amount of the active substance (45.4% of the total dose)
in 15 minutes is obtained, an interval of about 7 hours and 30
minutes during which a negligible amount of active substance is
released and the subsequent fast release of the second quantity of
active substance after 8 hour from the beginning of the dissolution
test. Such a behaviour fully answers the aims of the present
invention.
EXAMPLE 7
Preparation of a series of (5,000) tablets as in FIG. 2, containing
a mixture of Levodopa and Carbidopa as active substance.
7-a--Preparation of the Granulate for the Layer 1
A first granulate is prepared which will be used in the preparation
of the layer 1. The layer 1 contains 30 mg of Carbidopa and 30 mg
of Levodopa and shows the following unit composition:
Carbidopa monohydrate = 30 mg of Carbidopa (Alfa Chem, 32.4 mg
Milan, I) Levodopa (Alfa Chem, Milan, I) 30.0 mg Microcrystalline
cellulose (Avicel PH 102, FMC, 99.2 mg Philadelphia, USA) Green
lacquer + yellow lacquer (Eigenmann-Veronelli, 0.2 mg Milan, I)
Polyvinylpyrrolidone (Plasdone.sup.R K 30, ISP, Wayne, NY, 4.8 mg
USA) Carboxymethylstarch (Explolab.sup.R, Mendell, Carmel, NY, 12.0
mg USA) Talc (C. Erba, Milan, I) 6.9 mg Magnesium stearate (C.
Erba, Milan, I) 2.4 mg Colloidal silica (Syloid 244, Grace GmbH,
Worms, D) 1.2 mg Total 188.2 mg
In a sigma Erweka K5 type mod. (Frankfurt am M., D) mixer, the
proper amounts of the two active substances with the
microcristalline cellulose and the two dyes are mixed; the mixture
is wet with a 10% (w/v) hydro-alcoholic solution of
polyvinylpyrrolidone and the homogeneously wet mass is forced onto
a 25 mesh (710 .mu.m) grid obtaining a regular granulate which is
dried in a 40-45.degree. C. air circulation stove. The granulate,
dried to a constant weight, is placed in a Turbula T2A mod.
(Bachofen--Basel--CH) powder mixer, added with carboxymethylstarch
and mixed for 20 minutes. Talc, magnesium stearate and colloidal
silica are then added to the mixture and the mixing is carried out
for further 20 minutes. The granulate undergoes the compression as
described below.
7-b--Preparation of the Granulate for the Layer 3
A second granulate which will be used in the preparation of the
layer 3 is prepared. The layer 3 contains 25 mg of Carbidopa and
100 mg of Levodopa and shows the following unit composition:
Carbidopa monohydrate = 25 mg of Carbidopa (Alfa Chem, 27.0 mg
Milan, I) Levodopa (Alfa Chem, Milan, I) 100.0 mg Microcristalline
cellulose (Avicel PH 102, FMC, 50.0 mg Philadelphia, USA) Green
lacquer (Eigenmann-Veronelli, Milan, I) 0.1 mg Polyvinylpyrrolidone
(Plasdone.sup.R K30, ISP, Wayne, NY, 6.0 mg USA)
Carboxymethylstarch (Explotab.sup.R, Mendell, Carmel, NY, 14.0 mg
USA) Talc (C. Erba, Milan, I) 6.0 mg Magnesium stearate (C. Erba,
Milan, I) 4.0 mg Colloidal silica (Syloid 244, Grace GmbH, Worms,
D) 1.0 mg Total 208.0 mg
In a sigma Erweka K5 type mod. (Frankfurt am M., D) mixer the
proper amounts of the two active principles with the
microcristalline cellulose and the dye are mixed; the mixture is
wet with a 10% (w/v) hydro-alcoholic solution of
polyvinylpyrrolidone and the homogeneously wet mass is forced onto
a 25 mesh (710 .mu.m) grid obtaining a regular granulate which is
dried in a 40-45.degree. C. air circulation stove. The granulate,
dried to a constant weight, is placed in a Turbula T2A mod.
(Bachofen--Basel--CH) powder mixer, added with carboxymethylstarch
and mixed for 20 minutes. Talc, magnesium stearate and colloidal
silica are then added to the mixture and the mixing is carried out
for further 20 minutes. The granulate, undergoes compression as
described below.
7-c--Preparation of the Granulate for the Barrier Layer 2
The preparation is carried out as reported in example 3 at point
3-b.
7-d--Preparation of the Three Layer Cores (by compression)
The granulate obtained according to what previously reported is
loaded into the three hoppers of a rotating compressing machine
suitable to produce three layer tablets (e.g. Manesty Layer-Press,
Liverpool, UK). In particular in the first hopper the granulate
described at point 7-a is loaded, in the second hopper the
granulate described at point 7-c is loaded and the third hopper is
filled with the granulate described at point 7-b.
The compressing machine is equipped with circular convex punches
having a diameter equal to 9 mm and R=12 mm. The machine is
adjusted to produce three layers cores of which the layer 1 is
formed by 188.2 mg of granulate 7-a containing 30 mg of Carbidopa
and 30 mg of Levodopa, the layer 2 consists of 130 mg of the
granulate 7-c (such an amount being necessary to obtain a thickness
of about 1.2 mm) and the layer 3 is constituted by 208.0 mg of
granulate 7-b containing 25 mg of Carbidopa and 100 mg of
Levodopa.
Operating as previously described, three layers cores are obtained
having an average weight equal to 526.2 mg containing two distinct
amounts of the association of the two active substances for a total
of 55 mg of Carbidopa and 130 mg of Levodopa. The cores so obtained
undergo a second compression stage for the application of the
coating using the granulate described at point 7-e.
7-e--Preparation of the Granulate for the External Coating
The preparation is carried out as reported in example 1 at point
1-d.
7-f--Coating by Compression
The coating is carried out as reported in example 1 at point 1-e.
Tablets, as illustrated in FIG. 2, are obtained consisting of three
layers cores (two out of three layers contain two different amounts
of the association of the two active substances: Carbidopa and
Levodopa), coated on the surface except the upper face constituted
by the first layer showing fast release of the first fraction of
active substances.
7-g--Dissolution Test
In order to estimate the release characteristics of the tablets the
equipment 2, paddle (described in USP XXII) is used operating at
100 r.p.m. and using deionized water at 37.degree. C. as the
dissolution fluid. The release of the two active substances is
followed by U.V. spectrophotometric determination at 280 nm using
an automatic sampling and reading system (Spectracomp 602, Advanced
Products--Milan, I).
The results are reported in Table VII.
TABLE VII TIME (min) % Carbidopa released % Levodopa released 15
53.9 21.0 30 55.4 23.0 60 55.6 23.2 90 55.9 23.4 120 56.0 23.6 150
58.0 27.2 180 98.2 97.6 210 99.3 99.2 240 100.2 99.9
It is possible to point out that from the tablets a fast release of
the first amount of Carbidopa (equal to 53.9% of the total dose) in
15 minutes is obtained, an interval of about 60-90 minutes during
which a negligible amount of active substance is released and the
subsequent fast release of the second amount of Carbidopa after 2
hours from the beginning of the dissolution test. At the same time
a fast release of the first amount of Levodopa (equal to 21% of the
total dose) in 15 minutes is obtained, an interval of about 2 hours
and 20 minutes during which a negligible amount of active substance
is released and the subsequent fast release of the second quota of
Levodopa after 3 hours from the beginning of the dissolution
test.
Such a behavior fully answers the aims of the present
invention.
* * * * *